This invention concerns a method for preparing a physically stable and homogenous powdered preparation containing in particulated form an active agent and optionally conventional physiologically acceptable additives, such as a carrier.
Powder inhalers are widely used for ozone-saving dosing of active drugs into the lungs. These devices can be divided in two categories:
1. Devices provided with a powder reservoir and means for metering a dose from the reservoir for each delivery to the patient
2. Devices provided with pre-metered powder doses in capsules, blisters etc.
The performance of any powder inhaler must fulfill the requirements of Pharmacopeias for delivered dose uniformity (xc2x125% of mean). Also the mass of respirable particles per dose and general stability of the formulation must be documented and accepted by the authorities.
Concerning inhalation, the respirable particles are commonly accepted to be particles having an aerodynamic diameter less than 6 microns, which can be tested in a laboratory.
Dry powders for inhalation are normally manufactured of micron size drug particles and a coarser carrier, e.g. lactose or glucose, by mixing them in a dry homogenizer. All micron size particles are very cohesive and tend to adhere strongly to each other and other surfaces (carrier, container, and the like). Therefore, special care must be paid in the mixing process in order to obtain a homogenous blend. A non-homogenous blend will cause variations in the delivered dose, especially with reservoir devices, which additionally show a natural variation in accuracy of metering the dose.
When a dose is inhaled a part of the micron sized drug particles is separated from the carrier. Only particles this small deposit in the lung. If the forces adhering the drug particles onto other drug particles or carrier particles is increased, the amount of respirable particles will decrease and the clinical effect will be different. Altered adhesion also affects dose metering accuracy in reservoir devices.
A common reason for agglomeration of an inhalation powder is that some substances, often the drug, are in an unstable state. Such instability is mainly caused by polymorphic crystals or amorphous matter, which tend to recrystalize in a thermodynamically most stable state. Simultaneously, micron size particles tend to fuse together and adhere on any available surfaces. Such changes take place slowly at normal room temperatures but are commonly accelerated by elevated temperature, presence of moisture or organic vapours.
Polymorphic crystals may form during crystallization but a proper choice of solvent may prevent it. Amorphous material is normally formed during high-energy treatment of organic solids, e.g. micronization in a jet-mill or ball-mill, or in rapid precipitation with anti-solvent or during spray-drying. Carrier substances may contain amorphous matter as well.
As a summary, a manufacturing method resulting in excellent homogeneity of physically stable substances is well established.
The presence and characteristics of amorphous matter in micronized drug particles has been shown in several publications (e.g. with salbutamol by Ward and Schulz in Pharmaceutical Research, Vol. 12, No 5, 1995).
In WO 95/05805 a micronized drug or a mixture containing a micronized drug is stabilized by using water vapour preferably at 10-50xc2x0 C. and over 75% relative humidity. This method is useful for water soluble substances. If the mixture contains water insoluble substances, vapour treatment with organic solvents should be carried out, too. Stabilization of dry powder is using vapour and no wet suspension is mentioned. The authors suppose that, as a rule, water soluble substances must be treated with water vapour and water insoluble substances with organic vapour.
In PCT/SE92/00186 a micronized water soluble drug is stabilized in a similar manner with ethanol, acetone or other organic vapours. Prior to the treatment all water was removed from the drug at elevated temperature and under vacuum. After the treatment residues of organic solvent were removed from the drug with an inert gas. No suspension treatment is mentioned.
There are some drawbacks in treating dry powders. During vapour stabilization, the particles obviously tend to fuse together to some extent, which must be controlled. Adequate care must be paid to prevent contamination of drug during the treatment.
Suspension of an active drug in a volatile solvent in making a powder for inhalation is mentioned in U.S. Pat. No. 5,503,869. Here only micronized drug is suspended in HFA-propellants in order to fix an exact dose on a carrier net of metal, plastic, ceramic or similar material. When the propellant is evaporated, the drug can be blown into the air to be inhaled. No stabilization of the drug is mentioned.